The metabolic influence of gut microbiota plays a pivotal role in the pathogenesis of cardiometabolic diseases. Antibiotics affect intestinal bacterial diversity, and long-term usage has been ...identified as an independent risk factor for atherosclerosis-driven events. The aim of this study was to explore the interaction between gut dysbiosis by antibiotics and metabolic pathways with the impact on atherosclerosis development.
We combined oral antibiotics with different diets in an Apolipoprotein E-knockout mouse model linking gut microbiota to atherosclerotic lesion development via an integrative cross-omics approach including serum metabolomics and cecal 16S rRNA targeted metagenomic sequencing. We further investigated patients with carotid atherosclerosis compared to control subjects with comparable cardiovascular risk.
Here, we show that increased atherosclerosis by antibiotics was connected to a loss of intestinal diversity and alterations of microbial metabolic functional capacity with a major impact on the host serum metabolome. Pathways that were modulated by antibiotics and connected to atherosclerosis included diminished tryptophan and disturbed lipid metabolism. These pathways were related to the reduction of certain members of Bacteroidetes and Clostridia by antibiotics in the gut. Patients with atherosclerosis presented a similar metabolic signature as those induced by antibiotics in our mouse model.
Taken together, this work provides insights into the complex interaction between intestinal microbiota and host metabolism. Our data highlight that detrimental effects of antibiotics on the gut flora are connected to a pro-atherogenic metabolic phenotype beyond classical risk factors.
•Antibiotics exacerbate atherosclerosis independently of diet.•Gut microbiota and metabolic alpha diversity are reduced by antibiotics.•Pathways connected to atherogenesis are tryptophan and lipid metabolism.•Metabolic changes are linked to reduced Clostridia and Bacteroidetes in the gut.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but ...its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.
BACKGROUND—High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors.
METHODS AND RESULTS—We applied quantitative nuclear magnetic ...resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women’s Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyseshigher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12–1.24; P=4×10) and monounsaturated fatty acid levels (1.17; 1.11–1.24; P=1×10) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84–0.94; P=6×10) and docosahexaenoic acid levels (0.90; 0.86–0.95; P=5×10) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289).
CONCLUSIONS—Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.
The metabolome, although very dynamic, is sufficiently stable to provide specific quantitative traits related to health and disease. Metabolomics requires balanced use of state-of-the-art study ...design, chemical analytics, biostatistics, and bioinformatics to deliver meaningful answers to contemporary questions in human disease research. The technology is now frequently employed for biomarker discovery and for elucidating the mechanisms underlying endocrine-related diseases. Metabolomics has also enriched genome-wide association studies (GWAS) in this area by providing functional data. The contributions of rare genetic variants to metabolome variance and to the human phenotype have been underestimated until now.
Metabolomics provides versatile functional phenotyping.
The dynamics of the metabolome reflects gene–gene as well as gene–environment interactions.
Distinct environmental challenges including nutrition, medication, and age reveal specific metabolomic signatures.
Multiple endocrine disorders reveal unique metabolite signatures.
Metabolomics-derived biomarkers have high potential for use in precision medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAT) compared to subcutaneous sites (SAT) has been suspected as a ...key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAT or SAT amount among subjects free of metabolic diseases to identify possible contributing metabolic pathways. The study population comprised 491 subjects mean (standard deviation): age 44.6 yrs (13.0), body mass index 25.4 kg/m² (3.6), 60.1% females without diabetes, hypertension, dyslipidemia, the metabolic syndrome or impaired renal function. We associated MRI-derived fat amounts with mass spectrometry-derived metabolites in plasma and urine using linear regression models adjusting for major confounders. We tested for sex-specific effects using interactions terms and performed sensitivity analyses for the influence of insulin resistance on the results. VAT and SAT were significantly associated with 155 (101 urine) and 49 (29 urine) metabolites, respectively, of which 45 (27 urine) were common to both. Major metabolic pathways were branched-chain amino acid metabolism (partially independent of insulin resistance), surrogate markers of oxidative stress and gut microbial diversity, and cortisol metabolism. We observed a novel positive association between VAT and plasma levels of the potential pharmacological agent piperine. Sex-specific effects were only a few, e.g. the female-specific association between VAT and O-methylascorbate. In brief, higher VAT was associated with an unfavorable metabolite profile in a sample of healthy, mostly non-obese individuals from the general population and only few sex-specific associations became apparent.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy.
SGLT2 inhibition is a new strategy to treat diabetes. In the ...EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart.
We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress.
Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected.
In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.
•Effects of empagliflozin dependent SGLT2i on glucose metabolism, cardiac function and substrate utilization in db/db mice.•Empagliflozin improved glucose metabolism, survival and left ventricular diastolic function of db/db mice.•Systemic levels of ketone bodies or cardiac expression of enzymes for ketone body or BCAA catabolism were not affected.•Beneficial effect of empagliflozin might be mediated by improved cardiomyocyte Ca2+ handling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SMs) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related ...to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM.
Methods
We performed untargeted metabolomics on serum samples obtained from patients with IS (N = 508) and SM (N = 349; defined by absence of a diffusion weighted imaging DWI positive lesion on magnetic resonance imaging MRI) who presented to the hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling = 3.3 hours; interquartile range IQR = 1.6–6.7 hours) and from neurologically normal controls (NCs; N = 112). We compared diagnostic groups in a discovery‐validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look‐up of published metabolite sets.
Results
Levels of 41 metabolites were significantly associated with IS compared to NCs. The top metabolites showing the highest value in separating IS from SMs were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these 4 metabolites differentiated patients with IS from SMs with an area under the curve (AUC) of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (CT; AUC = 0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All 4 metabolites returned to control levels by day 90.
Interpretation
A set of 4 metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival, thus encouraging further investigation, including multicenter studies. ANN NEUROL 2020;88:736–746
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using ...high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.
Synopsis
This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.
Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.
Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.
Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy.
This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is an important biomarker for the diagnosis of heart failure. Apart from this and only recently recognized, NT-proBNP levels ...associate with higher HDL- and lower LDL-cholesterol levels comprising a favorable blood lipid profile. To further examine this observation, the lipoprotein profile in relation to NT-proBNP was examined in-depth by proton nuclear magnetic resonance spectroscopy (
H-NMR). We complemented this investigation with a state-of-the-art untargeted metabolomics approach.
Lipoprotein particles were determined by
H-NMR spectroscopy in 872 subjects without self-reported diabetes from the population-based Study of Health in Pomerania (SHIP)-TREND with available NT-proBNP measurements. Comprehensive metabolomics data for plasma and urine samples were obtained. Linear regression models were performed to assess the associations between serum concentrations of NT-proBNP and the metabolites/lipoprotein particles measured in plasma or urine.
An increase in serum NT-proBNP was associated with a benefical lipoprotein profile, including a decrease in VLDL, IDL and LDL-particles along with an increase in large HDL particles. These findings were replicated in a second independent cohort. Serum concentrations of NT-proBNP showed significant inverse associations with seven plasma metabolites while associations with 39 urinary metabolites, mostly comprising amino acids and related intermediates, were identified. Mediation analyses revealed adiponection as mediating factor for the associations observed with lipoproteins particles.
Most of the metabolic changes associated with NT-proBNP implicate significant influence on the blood lipid profile besides vasodilatory and the diuretic action of BNP signaling. Our data suggest that the more favorable lipoprotein profile as associated with elevated NT-proBNP concentrations in mainly cardiac healthy individuals might relate to adiponectin signaling indicating even indirect cardio-protective effects for NT-proBNP.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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